Jeffrey I Cohen

National Institute of Allergy and Infectious Diseases, Maryland, United States

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Publications (128)810.18 Total impact

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    ABSTRACT: No Herpes simplex virus type-2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular injection of HSV-2 gB and gD proteins in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) and gD (gDsec), but not PsV expressing cytoplasmic or membrane-bound forms, induced circulating and intravaginal tissue resident memory CD8(+) T cells able to secrete IFN-γ and TNF-α and moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec/gDsec vaccines conferred improved survival after HSV-2 vaginal challenge compared to HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with reduced severity of genital lesions and lower viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with soluble HSV-2 gD in alum and monophosphoryl lipid A (gD2t/Alum/MPL) elicited high neutralizing antibody titers and improved survival, but did not reduce genital lesions and viral shedding. Vaccination combining HPV-gBsec/gDsec ivag and gD2t/Alum/MPL i.m. improved survival and reduced genital lesions and viral shedding. Finally, circulating HSV-2-specific CD8(+) T cells, not serum antibodies, correlated with reduced viral shedding. Together our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.
    Journal of virology. 10/2014;
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    ABSTRACT: A high-throughput test to detect varicella-zoster virus (VZV) antibody in varicella vaccine recipients is not available. One of the most sensitive tests to detect VZV antibodies after vaccination is the fluorescent antibody to membrane antigen test (FAMA). Unfortunately, this test is labor intensive, somewhat subjective to read, and not commercially available. Therefore, we developed a highly quantitative and high-throughput luciferase immunoprecipitation systems (LIPS) assay to detect antibody to VZV glycoprotein E (gE). Testing of children who received the varicella vaccine showed that the gE LIPS assay had 90% sensitivity and 70% specificity, a viral capsid antigen ELISA assay had 67% and 87% specificity, and a glycoprotein ELISA (not commercially available in the US) had 94% sensitivity and 74% specificity, compared with the FAMA test. Rates of antibody detection by the gE LIPS and glycoprotein ELISA were not statistically different. Therefore, the gE LIPS assay may be useful for detecting VZV antibody in varicella vaccine recipients.
    Clinical and vaccine Immunology: CVI 07/2014; · 2.60 Impact Factor
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    ABSTRACT: Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 05/2014; · 3.12 Impact Factor
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    ABSTRACT: Herpesvirus capsid morphogenesis occurs in the nucleus, while final maturation takes place in the cytosol requiring translocation of capsids through the nuclear envelope. The nuclear egress complex consisting of homologs of herpes simplex virus pUL31 and pUL34, is required for efficient nuclear egress via primary envelopment-deenvelopment. Recently, we described an alternative mode of nuclear escape by fragmentation of the nuclear envelope induced by replication competent pUL31 and pUL34 deletion mutants of the alphaherpesvirus pseudorabies virus (PrV), which had been selected by serial passaging in cell culture. Both passaged viruses carry congruent mutations in seven genes including UL46 which encodes one of the major tegument proteins. Herpesvirus pUL46 homologs have recently been shown to activate the PI3K-Akt and ERK1/2 signaling pathways, which are involved in regulation of mitosis and apoptosis. Since in uninfected cells fragmentation of the nuclear envelope occurs during mitosis and apoptosis, we analyzed whether pUL46 of PrV is involved in signaling events impairing the integrity of the nuclear envelope. We show here that PrV pUL46 is able to induce phosphorylation of ERK1/2 and, thus, expression of ERK1/2 target genes, but fails to activate the PI3K-Akt pathway. Deletion of UL46 from PrV-ΔUL34Pass and PrV-ΔUL31Pass, or substitution by wild type UL46 resulted in enhanced nuclear envelope breakdown indicating that the mutations in pUL46 may limit the extent of NEBD. Thus, although pUL46 induces ERK1/2 phosphorylation, controlling the integrity of the nuclear envelope is independent of the ERK1/2 signaling pathway. Herpesvirus nucleocapsids can leave the nucleus by regulated, vesicle-mediated transport through the nuclear envelope designated as nuclear egress, or by inducing nuclear envelope breakdown (NEBD). The viral proteins involved in NEBD are unknown. We show here that the pseudorabies virus tegument protein pUL46 induces the ERK1/2 signaling pathway and modulates NEBD. However, these two processes are independent and ERK1/2 signaling induced by pUL46 is not involved in herpesvirus-induced NEBD.
    Journal of Virology 03/2014; · 5.08 Impact Factor
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    Vaccine 01/2014; · 3.77 Impact Factor
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    ABSTRACT: Mammalian cells activate DNA damage response pathways in response to virus infections. Activation of these pathways can enhance replication of many viruses, including herpesviruses. Activation of cellular ATM results in phosphorylation of H2AX and recruits proteins to sites of DNA damage. We found that varicella-zoster (VZV) infected cells had elevated levels of phosphorylated H2AX and phosphorylated ATM and that these levels increased in cells infected with VZV deleted for ORF61 or ORF63, but not deleted for ORF67. Expression of VZV ORF61, ORF62, or ORF63 alone did not result in phosphorylation of H2AX. While BGLF4, the Epstein-Barr virus homolog of VZV ORF47 protein kinase, phosphorylates H2AX and ATM, neither VZV ORF47 nor ORF66 protein kinase phosphorylated H2AX or ATM. Cells lacking ATM had no reduction in VZV replication. Thus, VZV induces phosphorylation of H2AX and ATM and this effect is associated with the presence of specific VZV genes in virus-infected cells.
    Virology 01/2014; s 452–453:52–58. · 3.35 Impact Factor
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    ABSTRACT: Background Human cytomegalovirus (HCMV) infection can cause severe disease in neonates and immunocompromised persons, and infectious mononucleosis in healthy adults. While, rhesus CMV (RhCMV) infects human cells in culture, it is unknown whether the virus can infect humans. Objectives We sought to determine whether primate workers, including those with injuries from animals, might be infected asymptomatically with RhCMV. Study design We developed serologic assays that distinguish RhCMV from HCMV antibodies. We tested two groups of primate workers: those with documented injuries or mucosal splashes associated with rhesus macaques, and those with no documented exposure who worked with these animals. Results None of over 200 primate workers, including 119 with injuries or mucosal splashes associated with exposures to macaques, were seropositive for RhCMV. Conclusions The frequency of asymptomatic RhCMV infection in persons who work with rhesus macaques was <0.5% (<1/200 primate workers).
    Journal of Clinical Virology. 01/2014;
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    ABSTRACT: Rhesus cytomegalovirus (RhCMV) 68-1 is the prototypic strain of RhCMV that has been used for pathogenesis and vaccine development. We determined the complete sequence of the RhCMV 68-1 UL/b' region directly from the original urine from which RhCMV 68-1 was isolated in 1968, and compared it to other RhCMVs. The laboratory passaged RhCMV 68-1 has inversions, deletions, and stop codons in UL/b' that are absent in the original isolate and other low passage RhCMV isolates. Fourteen of the 17 open reading frames (ORFs) in 68-1 UL/b' in the original isolate share >95% amino acid identity with low passage RhCMV. The original isolate retains 6 ORFs that encode α-chemokine-like proteins, including RhUL146 and RhUL146b that share only 92% and 81% amino acid identity, respectively, with a contemporary low passage RhCMV isolate. Identification of the original RhCMV 68-1 UL/b' sequence is important for using RhCMV 68-1 in pathogenesis and vaccine studies.
    Virology 12/2013; 447(1-2):208-12. · 3.35 Impact Factor
  • Xueqiao Liu, Jeffrey I Cohen
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    ABSTRACT: Programmed cell death (apoptosis) is an important host defense mechanism against intracellular pathogens such as viruses. Accordingly, viruses have evolved multiple mechanisms to modulate apoptosis to enhance replication. VZV induces apoptosis in human fibroblasts and melanoma cells. We found that VZV triggered the phosphorylation of pro-apoptotic proteins Bim and BAD, but had little or no effect on other Bcl-2 family members. Since phosphorylation of Bim and BAD reduce their pro-apoptotic activity, this may prevent or delay apoptosis in VZV-infected cells. Phosphorylation of Bim, but not BAD, in VZV-infected cells was dependent on activation of the MEK/ERK pathway. Cells knocked-down for Bim showed delayed VZV plaque formation resulting in longer survival of VZV-infected cells and increased replication of virus, compared with wild-type cells infected with virus. Conversely, overexpression of Bim resulted in earlier plaque formation, smaller sized plaques, reduced virus replication, and increased caspase 3 activity. Inhibition of caspase activity in VZV-infected cells overexpressing Bim restored levels of virus production similar to those seen with virus-infected wild-type cells. Previously we showed that VZV ORF12 activates ERK and inhibits apoptosis in virus-infected cells. Here we found that VZV ORF12 contributes to Bim and BAD phosphorylation. In summary, VZV triggers Bim phosphorylation; reduction of Bim levels results in longer survival of VZV-infected cells and increased VZV replication.
    Journal of Virology 11/2013; · 5.08 Impact Factor
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    ABSTRACT: The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.
    Nature Immunology 10/2013; · 26.20 Impact Factor
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    ABSTRACT: The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg(2+)) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg(2+) causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8(+) T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg(2+) and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg(2+) in eukaryotic cells.
    Science 07/2013; 341(6142):186-191. · 31.20 Impact Factor
  • Journal of the American Academy of Dermatology 06/2013; 68(6):1046-7. · 4.91 Impact Factor
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    Blood 03/2013; 121(12):2364-6. · 9.78 Impact Factor
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    ABSTRACT: Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia, B and NK cell lymphopenia associated with opportunistic infections and cancers. In addition, patients suffer from recurrent and severe viral infections. NK cells play a critical role in mediating anti-viral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2 deficient patients and extend this genetic lesion to what is considered to be the original NK cell deficient patient. In most cases GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2 deficient patients are exclusively of the CD56(dim) subset, which is recapitulated upon in vitro NK cell differentiation. In vivo IFNα treatment increased NK cell number and partially restored function, but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.
    Blood 01/2013; · 9.78 Impact Factor
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    ABSTRACT: Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons. We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren's syndrome (SjS) to determine if their antibody profiles differed from control subjects. The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005), and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls. The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.
    PLoS ONE 01/2013; 8(12):e81635. · 3.53 Impact Factor
  • Lesia K Dropulic, Jeffrey I Cohen
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    ABSTRACT: HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies.
    Expert Review of Vaccines 12/2012; 11(12):1429-40. · 4.22 Impact Factor
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    Xueqiao Liu, Jeffrey I Cohen
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    ABSTRACT: VZV activates the phosphoinositide 3-kinase (PI3K)-Akt pathway and alters cell cycle progression, but the viral protein(s) responsible for these activities is unknown. We previously reported that VZV ORF12 protein triggers phosphorylation of ERK. Here we demonstrate that VZV ORF12 protein also activates the PI3K/Akt pathway to regulate cell cycle progression. Transfection of cells with a plasmid expressing the ORF12 protein induced phosphorylation of Akt which was dependent on PI3K. Infection of cells with wild-type VZV triggered phosphorylation of Akt, while infection with an ORF12 deletion mutant induced less phosphorylated Akt. The activation of Akt by ORF12 protein was associated with its binding to the p85 subunit of PI3K. Infection of cells with wild-type VZV resulted in increased levels of cyclin B1, cyclin D3 and phosphorylated GSK-3β, while infection with the ORF12 deletion mutant induced lower levels of these proteins. Wild-type VZV infection reduced the G1 phase cell population, and increased the M phase cell population, while infection with the ORF12 deletion mutant had a reduced effect on the G1 and M phase populations. Inhibition of Akt activity with LY294002 reduced the G1 and M phase differences observed in cells infected with wild-type and ORF12 mutant viruses. In conclusion, we find that the VZV ORF12 protein activates the PI3K/Akt pathway to regulate cell cycle progression. Since VZV replicates in both dividing (e.g. keratinocytes) and non-dividing (neurons) cells, the ability of VZV ORF12 protein to regulate the cell cycle is likely important for VZV replication in various cell types in the body.
    Journal of Virology 11/2012; · 5.08 Impact Factor
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    ABSTRACT: ABSTRACT Ascorbic acid has been shown to kill various cancer cell lines at pharmacologic concentrations. We found that Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) cells were more susceptible to ascorbic acid-induced cell killing than EBV-negative BL cells or EBV-transformed lymphoblastoid cells (LCLs). Ascorbic acid did not induce apoptosis in any of the tested cells but did induce the production of reactive oxygen species and cell death. Previously, we showed that bortezomib, a proteasome inhibitor, induces cell death in LCLs and EBV-positive BL cells. We found that ascorbic acid is strongly antagonistic for ascorbic acid-induced cell death in LCLs and EBV-positive BL cells. Finally, ascorbic acid did not prolong survival of severe combined immunodefiency mice inoculated with LCLs either intraperitoneally or subcutaneously. Thus, while ascorbic acid was highly effective at killing EBV-positive BL cells and LCLs in vitro, it antagonized cell killing by bortezomib and was ineffective in an animal model.
    Leukemia & lymphoma 10/2012; · 2.61 Impact Factor
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    ABSTRACT: We constructed a herpes simplex virus 2 (HSV-2) bacterial artificial chromosome (BAC) clone, bHSV2-BAC38, which contains full length HSV-2 inserted into a BAC vector. Unlike previously reported HSV-2 BAC clones, the virus genome inserted into this BAC clone has no known gene disruptions. Virus derived from the BAC clone had a wild-type phenotype for growth in vitro, and for acute infection, latency, and reactivation in mice. HVEM, expressed on epithelial cells and lymphocytes, and nectin-1, expressed on neurons and epithelial cells, are the two principal receptors used by HSV to enter cells. We used the HSV2 BAC clone to construct an HSV-2 glycoprotein D mutant (HSV2-gD27) with point mutations in amino acids 215, 222, and 223 which are critical for the interaction of gD with nectin-1. HSV2-gD27 infected cells expressing HVEM, including a human epithelial cell line. However, the virus lost the ability to infect cells expressing only nectin-1, including neuronal cell lines, and did not infect ganglia in mice. Surprisingly, we found that HSV2-gD27 could not infect Vero cells, unless we transduced the cells with a retrovirus expressing HVEM. High level expression of HVEM in Vero cells also resulted in increased syncytia and enhanced cell-to-cell spread in cells infected with wild-type HSV-2. The inability of the HSV2-gD27 mutant to infect neuronal cells in vitro or sensory ganglia in mice after intramuscular inoculation suggests that this HSV-2 mutant might be an attractive candidate for a live attenuated HSV-2 vaccine.
    Journal of Virology 09/2012; · 5.08 Impact Factor
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    ABSTRACT: Progressive vaccinia (PV) is a rare but potentially lethal complication that develops in smallpox vaccine recipients with severely impaired cellular immunity. We describe a patient with PV who required treatment with vaccinia immune globulin and who received 2 investigational agents, ST-246 and CMX001. We describe the various molecular, pharmacokinetic, and immunologic studies that provided guidance to escalate and then successfully discontinue therapy. Despite development of resistance to ST-246 during treatment, the patient had resolution of PV. This case demonstrates the need for continued development of novel anti-orthopoxvirus pharmaceuticals and the importance of both intensive and timely clinical and laboratory support in management of PV.
    The Journal of Infectious Diseases 08/2012; 206(9):1372-85. · 5.85 Impact Factor

Publication Stats

3k Citations
810.18 Total Impact Points

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Institutions

  • 1997–2014
    • National Institute of Allergy and Infectious Diseases
      • • Laboratory of Parasitic Diseases (LPD)
      • • Laboratory of Immunoregulation
      Maryland, United States
  • 1995–2013
    • National Institutes of Health
      • • Laboratory of Infectious Diseases
      • • Laboratory of Clinical Infectious Diseases
      • • Laboratory of Sensory Biology
      • • National Institute of Allergy and Infectious Diseases (NIAID)
      • • Laboratory of Clinical Investigation (LCI)
      Maryland, United States
  • 2008
    • Fox Chase Cancer Center
      Philadelphia, Pennsylvania, United States
  • 2006
    • University of Colorado
      • Department of Neurology
      Denver, CO, United States
  • 2005
    • Harvard Medical School
      Boston, Massachusetts, United States
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2004
    • Saint Louis University
      • School of Medicine
      Saint Louis, MI, United States
  • 1999
    • University of California, Los Angeles
      Los Angeles, California, United States